scholarly journals Connect MM®—the Multiple Myeloma (MM) Disease Registry: Incidence of Second Primary Malignancies (SPM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4749-4749
Author(s):  
Robert M. Rifkin ◽  
Rafat Abonour ◽  
Jatin J. Shah ◽  
Jayesh Mehta ◽  
Mohit Narang ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Board Of Directors ◽  
Solid Tumor ◽  
Research Funding ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Prior History ◽  
Advisory Committees ◽  
History Of

Abstract Background: Increased rates of SPM have been observed as newer cancer treatments have improved survival over the past 2 decades (Fraumeni et al. NCI, 2006). Higher incidence of specific types of hematologic SPM following MM, especially acute myeloid leukemia and myelodysplastic syndromes, have been reported relative to the general population (Dores et al. NCI, 2006; Mailankody et al. Blood, 2011; Ravazi et al. Blood, 2011; Landgren and Mailankody. Leukemia, 2014). A complex interplay between myeloma-, host-, environmental-, and treatment-related factors likely contributes to the increased incidence of SPM in MM. Connect MM is the first and largest prospective, observational, US-based, multicenter registry designed to characterize patients (pts), treatment patterns, and outcomes in newly diagnosed MM (NDMM) pts. Methods: Between September 2009 and November 2012,a total of 1493 NDMM pts were enrolled from 234 US sites within 2 mos of the first diagnosis of MM. Patient data were collected at baseline and each subsequent quarter using a standardized form. Invasive SPM included hematologic and solid tumor second cancers and non-invasive SPM were defined as non-melanoma skin cancers (NMSC). SPM incidence and incidence rate (IR; number of pts with SPM per 100 patient-yrs [PY]) were calculated for all pts and by exposure to specific treatments, including lenalidomide (LEN). PYs were calculated as the observation period from the start of treatment until the detection of the first reported SPM (per category), death, or end of follow-up (pt lost or data cutoff). Results: As of Dec 10, 2013, SPM data were available for 1493 NDMM pts. The median age was 67 yrs (range, 24-94 yrs), 82% of patients were white and 57% were male. Median follow-up was 29.0 mos (0-49 mos). The median OS of treated pts was 44.4 mos. Fifty pts did not receive treatment and had no SPM reported. A total of 74 of the 1443 treated pts (5.1%) reported SPM. Invasive SPM were observed in 51 pts (3.5%): 37 pts (2.6%) with solid tumors and 14 pts (1.0%) with hematologic SPM. Lung/bronchus and myelodysplastic syndromes were the most frequently reported solid tumor and hematologic SPM respectively. NMSC were reported for 26 pts (1.8%). 3 pts had both an invasive SPM and NMSC. The IRs for invasive, hematologic, and solid tumor SPM by LEN exposure are listed in Table 1. By multivariate analysis, the only significant risk factor for the occurrence of SPM was prior history of invasive malignancy. Demographics (including age, ethnicity, race, and gender), International Staging System stage, family history of myeloma or other cancers, history of smoldering MM or monoclonal gammopathy of unknown significance, or prior radiation therapy were not associated with the occurrence of SPM. Conclusions: This analysis shows that there was no increased risk of invasive SPM in this disease-specific registry of pts with NDMM. The risk of SPM for LEN exposed pts was not greater than that for pts not exposed to LEN. In addition, multivariate analysis indicated the only significant risk factor for SPM was prior history of invasive malignancy. As additional agents are approved for the treatment of MM and the length of pt survival increases, longer prospective observation with expanded enrollment on the registry will better characterize the occurrence of SPM in this pt population. Correlations with risk factors including age, pre-existing MDS, risk status, as well as type and duration of therapy will continue to be investigated. Table 1. Incidence rates (per 100 PYa) by treatment exposure IR per 100 PY (95% CI) SPM LEN-Exposed (n = 977) Non–LEN Exposed (n = 466) Invasive 0.85 (0.61-1.19) 1.16 (0.72-1.86) Hematologic 0.17 (0.08-0.36) 0.47 (0.22-0.99) Solid tumor 0.67 (0.46-0.98) 0.68 (0.36-1.26) NMSC 0.50 (0.32-0.77) 0.41 (0.18-0.91) a PY of exposure is the sum of exposure of all pts. Disclosures Rifkin: Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Shah:Celgene Corp: Consultancy, Research Funding. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Lu:Celgene Corp: Employment. Kenvin:Celgene Corp: Employment. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Durie:Celgene Corp: Expert Board Committee Other; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees; IRC J&J: Membership on an entity's Board of Directors or advisory committees.

Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-49
Author(s):  
Samantha Ferrari ◽  
Chiara Pagani ◽  
Mariella D'Adda ◽  
Nicola Bianchetti ◽  
Annamaria Pelizzari ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
High Risk ◽  
Board Of Directors ◽  
Advisory Board ◽  
Advisory Committees ◽  
Risk Status ◽  
History Of ◽  
Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=<0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3180-3180
Author(s):  
Felix Lopez-Cadenas ◽  
Blanca Xicoy ◽  
Silvia Rojas P ◽  
Kaivers Jennifer ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Rank Test ◽  
Advisory Committees ◽  
Disease Evolution ◽  
Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Safety and Efficacy of Venetoclax-Based Treatment in Elderly CLL Patients: A Retrospective Study from the Filo Group

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3747-3747
Author(s):  
Charlotte Doublet ◽  
Marie-Sarah Dilhuydy ◽  
Emmanuelle Ferrant ◽  
Pierre Feugier ◽  
Alexandra Fayault ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Oncology Nurses ◽  
Advisory Committees ◽  
Free Survival ◽  
Daily Dose ◽  
History Of

Abstract Median age at diagnosis of chronic lymphocytic leukemia is 72 years. However, only few patients over 80 years of age are included in clinical trials, even in those devoted to unfit patients. In order to evaluate both efficiency and safety of venetoclax in this category of patients, we conducted a multicentric retrospective study and collected data from 77 CLL patients from 19 FILO centers who started venetoclax after 80 years of age. Median age at venetoclax initiation was 86 years old (81-97). 63% of patients had a history of heart disease, 62% had renal failure (moderate 59% and severe 3%) and 29% had a history of severe infections. Despite their comorbidities and a CIRS greater than 6 in 70% of cases, their autonomy was preserved with a median performans status of 1 (0-4). In this comorbid geriatric population, pretherapeutic geriatric assessment was only performed in a single patient. The median number of prior therapies was 2 (0-6) with an exposure to a BCR inhibitor in 56% of cases. 11q and 17p deletion were found in 39% and 30% of cases respectively, 39% of patients had a complex karyotype and 30% harbored a TP53 mutation. However, in this real life population, these prognostic factors were only performed in half of patients. IGHV mutational status was only available in 11 patients, and 83% of them had unmutated IGHV. At the time of venetoclax initiation, the tumor lysis syndrome (TLS) risk was moderate in 57% of cases and high in 8% of cases. Venetoclax was administered as a single agent (42%) or in association with rituximab (58%). In total, half of the patients were hospitalized at each dose ramp-up, and only 3 patients were treated on outpatient basis. 82% of the cohort was able to reach the daily dose of 400mg. Half of the patients were included in a phone call monitoring program with oncology nurses to pre-emptively manage side effects and foster therapy adherence. The safety study reported 14% of TLS, with 2 discontinuations of treatment within the first month: one of which led to dialysis and the other to death. As in the previously published studies, 25% of patients had infectious complications, and grade 3 haematological and digestive toxicities were reported in 42% and 22% of cases, respectively. The reduction of the daily dose of venetoclax was necessary for 33%. Permanent discontinuation of venetoclax occurred in 40% of subjects, including 29% of early withdrawal (within the first 3 months). Main reasons for discontinuation were intolerance (21%), CLL progression (21%), death (21%) and scheduled treatment discontinuation (10%). The overall response rate was 86%, consisting of 49% of complete response (unconfirmed by bone marrow biopsy) and 37% of partial response. With a median follow-up of 21months, estimated progression free survival and overall survival were 29 and 38 months respectively. Prior exposure to a BCR inhibitor had no impact on progression free survival. To conclude, venetoclax has a manageable safety profile in elderly patients with comorbidities and can induce prolonged responses. Finally, if additional follow-up by oncology nurses seems to be more and more implemented, the pre-therapeutic onco-geriatric evaluation remains underexploited in this population. Disclosures Ferrant: AstraZeneca: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Other: Travel, Accommodations, Expenses. Feugier: Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria. Laribi: AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; AbbVie: Other: Personal Fees, Research Funding; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding. Tchernonog: JANSSEN: Consultancy; ABBVIE: Consultancy; ASTRAZENECA: Consultancy. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Quinquenel: Abbvie: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

Ponatinib In Patients (pts) With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Resistant Or Intolerant To Dasatinib Or Nilotinib, Or With The T315I BCR-ABL Mutation: 2-Year Follow-Up Of The PACE Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 650-650 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp D le Coutre ◽  
Ronald Paquette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Response Rates ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Common Drug ◽  
Heavily Pretreated ◽  
History Of

Abstract Background Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in the phase 2, international, open-label clinical trial (PACE) in pts with CML or Ph+ ALL. Methods 449 pts resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled. Five pts (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses only. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos for CP-CML, major hematologic response (MaHR) at any time within 6 mos for advanced Ph+ leukemia. Data are as of 1 April 2013, with a median follow-up of 19 (0.1-30) mos, and 18 mos minimum follow-up for pts remaining on study. Results Median age was 59 (18-94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3-28) yrs. Pts were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib, 7% bosutinib; 58% received ≥3 TKIs. In pts previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance, 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, 23% MaHR or better in advanced Ph+ leukemia. The most common BCR-ABL mutations at baseline were 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44% of pts (Sanger sequencing). At the time of analysis, 46% of pts remained on study (60% CP-CML). The most common reasons for discontinuation: progressive disease (20%), adverse events (AEs; 13%; most common was thrombocytopenia, 4%). Response rates are shown in the table. Response rates were higher in CP-CML T315I vs R/I cohorts, however, a post-hoc multivariate analysis previously showed that T315I was not an independent predictor of MCyR. Other features, especially higher dose intensity and younger age in T315I pts, may explain the higher response rates. In CP-CML, responses were deep and durable; 91%, 91%, and 75% of pts with MCyR, CCyR, or MMR, respectively, were estimated to remain in response at 12 mos; progression-free survival (PFS) and overall survival (OS) were estimated to be 80% (median 27 mos) and 94% at 12 mos, respectively; progression to AP/BP occurred in 3 CP-CML pts , 2 other pts with a history of AP re-entered AP. 49% of AP-CML pts with MaHR were estimated to remain in response at 12 mos (median 12 mos); PFS and OS were estimated to be 56% (median 14 mos) and 84% at 12 mos. 36% of BP-CML pts with MaHR were estimated to remain in response at 12 mos (median 5 mos); PFS and OS were estimated to be 18% (median 4 mos) and 30% (median 7 mos) at 12 mos. 8% of Ph+ ALL pts with MaHR were estimated to remain in MaHR at 12 mos (median 3 mos); PFS and OS were estimated to be 7% (median 3 mos) and 39% (median 8 mos) at 12 mos. The most common drug-related AEs (>30%) were thrombocytopenia (37%), rash (34%), and dry skin (32%). Pancreatitis was the most common drug-related serious AE (5%); it occurred early and was primarily managed with dose modification, 1 pt discontinued. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 3%, and 2% of pts (drug-related: 2%, 1%, 1%). Conclusions Ponatinib has substantial activity in these heavily pretreated Ph+ leukemia pts who have limited available treatment options, with a safety profile reflective of the population. Updated data with a minimum follow-up of 2 yrs will be presented. Disclosures: Cortes: Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD, BMS, Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Ariad, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees; Novartis, BMS, Teva: Speakers Bureau; Novartis, BMS, Teva, Pfizer, Ariad: Honoraria; Novartis & Bristol Myers Squibb: Research Funding; Novartis, Ariad and Teva: Consultancy. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Araid, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:Ariad, Novartis, BMS: Consultancy; Ariad, Novartis, BMS, Pfizer, Teva: Honoraria, Speakers Bureau. Müller:Novartis, BMS, Ariad: Consultancy, Honoraria; Novartis, BMS: Research Funding. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding.

Could Chronic Gvhd Overcome the Poor Prognosis of Patients with MDS and TP53 Undergoing Allogeneic HSCT?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2890-2890
Author(s):  
Juan Carlos Caballero ◽  
Mercedes Sánchez-Barba ◽  
Mónica Del Rey ◽  
Kamila Janusz ◽  
Eva Lumbreras ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Somatic Mutations ◽  
Advisory Committees ◽  
Poor Outcome

Abstract Background and Aim Although new agents have been approved for the treatment of MDS, the only curative approach for these patients is allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, in these patients this approach has only obtained 40-60% of overall survival. Somatic mutations in MDS have recently been analyzed in order to confirm clonally and also prognostic impact in MDS patients. In this regard, TP 53 mutated gene is present in MDS in less than 10% of patients and is associated with advanced disease and high-risk features. Recent studies confirms poor outcomes in patients with TP 53 mutated receiving allogeneic stem cell transplantation1,2. The present study try to analyze if the development of chronic graft versus host disease (cGVHD) could modify, due to graft versus leukemia effect, the adverse prognosis of these high-risk patients (TP53 mutated patients). Design and Methods <>Results of HSCT in 92 MDS patients from 5 centers in Spain were retrospectively studied. Samples were collected 1 month prior to transplant. 280ng of the genomic DNA from BM cells was screened for somatic mutations in TP53 gene. The study was done by NGS on a GS Junior Instrument (Roche) according to an amplicon sequencing design. For each sample, eight exons (4-11) were amplified with preconfigured primer plates provided within the IRON II study network. Data analysis, were carried out using the Sequence Pilot software version 3.5.2 (JSI Medical Systems) and GS Amplicon Variant Analyzer software, versions 2.7 and 2.9 (Roche Applied Science). Minimum coverage of sequenced exons was 100 reads and the sensitivity of variant detection was set to a lower limit of >2% for bidirectional reads. Only those variants that resulted in amino acid change in the protein sequence were considered. OS and RFS were calculated using the Kaplan-Meier method. The log-rank test was used for comparisons. All calculations were done using SPSS 18.0. Cumulative incidence of relapse was also calculated by xlstat version 2014 program. <>Results Median age was 54 years (17-69), 71.7% were "de novo" MDS and regarding IPSS, 53% were in the int-2/high-risk category. Other characteristics were in Table 1. In the pre-transplant evaluation, 15 patients out of 92 (16,3%) were TP 53 mutated. The mutations were located in exons 5, 6, 7, 8 and 10. These variations were present in a variable percentageof the cell population (3 to 84%). All mutations were specific nucleotide changes except for two cases. At the time of the last update, 16 patients had relapsed (17.4%) and 40 had died (43.5%). After a median follow up of 15.5 months, OS was 56.5%. Median OS for patients with mutated TP53 trend a toward to be shorter than survival for patients without mutated TP53 (median of 7 mo vs median not reached, respectively, p=0.156). Multivariate analysis for OS confirmed complex karyotype (HR 5,588, 95CI 1,794-17,407, p=0.003) and no developement of cGVHD (HR 3,531, 95IC 1,634-7,632, p=0.001) as predictors for poor outcome. Cumulative incidence of relapse was 20.3% (+/-4.3%) at 1 years. Mutational status of TP53 significantly influenced on relapse (53.3% +/-12.9% vs 13.7% +/-4% at 1 year for patients with vs without TP 53 mutation (Gray test=0.001, Figure 2). Regarding Relapse Free Survival (RFS), after a median of follow up of 17 months, RFS was 67.9% and as previously suggested, the presence of TP 53 mutation had an impact on RFS (41.7% for mutated (median RFS of 6 months) and 75% for non mutated patients (median RFS not reached), p=0.009). Multivariate analysis for RFS confirmed age (HR 1.054, 95CI 1.005-1.106, p=0.032) and TP 53 mutated (HR 3.054, 95IC 1.145-8.149, p=0.026) as predictors for lower RFS. Regarding 15 patients with mutated TP 53, 7 did relapsed and 9 had died. Developement of cGVHD showed a trend toward to improve outcome among TP 53 mutated patients, with a better OS and RFS for those developing cGVHD as compared to those who did not (OS of 55% vs 17% for patients with and without cGVHD, p=0.039, Figure 2 and RFS of 71% vs 50%, respectively, p=0.3). <>Conclusions Mutated TP53 pre-allo patients presents poor outcome as compared to not mutated, as previously described Bejar1 and Kim2. Nevertheless, the developement of cGVHD could overcome the adverse impact of this factor due to the developement of graft versus tumor efect, improving survival curves (OS and RFS) as compared to previous published results. Study supported by GRS-1033/A/14 P53. 1.-BŽjar, JCO 2014, 32(25). 2.-Kim, BBMT 2015, Epub ahead of print. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Sanz: JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau. Valcarcel:AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Díez-Campelo:CELGENE: Research Funding, Speakers Bureau; JANSSEN: Research Funding; NOVARTIS: Research Funding, Speakers Bureau.

scholarly journals French National Retrospective Cohort of Hairy-Cell Leukemias: Risk of Second Malignancies after 10 Years of Follow-up

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1537-1537
Author(s):  
Jérôme Paillassa ◽  
Edouard Cornet ◽  
Stephanie Noel ◽  
Cecile Tomowiak ◽  
Aline Schmidt ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Retrospective Cohort ◽  
Hematological Malignancies ◽  
Hematological Malignancy ◽  
Solid Cancer ◽  
Advisory Committees ◽  
History Of ◽  
History Of Cancer

Introduction: Hairy-cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with a favorable outcome thanks to treatment with purine analogues (PNA) like cladribine and pentostatin. Here, we updated the French national retrospective cohort of HCL after 10 years of follow-up, in order to evaluate the risk of second cancers in these patients. Methods: Data were collected up to June 2018 through a questionnaire sent to the members of the Société Française d'Hématologie, and centralized in the cohort database. We described the second malignancies observed during the follow-up, distinguishing second 'solid' cancers from second hematological malignancies. Then, using a Fine and Gray model, we performed a multivariate analysis in order to identify second cancer risk factors. Finally, to evaluate the excess of cancers in our cohort in comparison with the French general population, we calculated the standardized incidence ratio (SIR). Results: 279 patients (pts) from 19 centers were included in our retrospective cohort. The median age was 59 years old (range 29-88). 21% had an infectious disease at diagnosis, 23% had a familial history of cancer and 11% a personal history of cancer before HCL diagnosis. The median number of lines of treatments was 1 (0-7). PNA (cladribine or pentostatin) were the first therapeutic choice in frontline (75% of pts) and at relapse (69%). With a median follow-up of 127 months (2-413), the median overall survival for the overall study population was 328 months (95% CI 299-357) and the median relapse-free survival (RFS) was 136 months (95% CI 109-163). Pts treated with cladribine or pentostatin in first line had a statistically significant better RFS than pts treated with 'other' treatments (log rank test, p &lt; 0.001). The 10-year cumulative incidence of relapse was 39% (95% CI 33-46). Pts who received treatments other than PNA in first line had a higher risk of relapse (Gray's test, p &lt; 0.001). For pts receiving PNA in first and second lines, there was no difference in outcomes between those who switched PNA and those who did not. In this cohort, we observed 68 second malignancies during the follow-up: 49 solid cancers (most prevalent: prostate and non-melanoma skin cancers) and 19 hematological malignancies (most prevalent: monoclonal gammopathy of undetermined significance (MGUS) and myelodysplastic syndromes (MDS)). The median onset of second cancer, second solid cancer and second hematological malignancy from HCL diagnosis was 81 months, 99 months and 78 months, respectively. The median age at diagnosis of cancer, solid cancer and hematological malignancy was 70, 69 and 77 years old, respectively. Considering death as a competing risk, the 10-year cumulative incidence of cancer, solid cancer and hematological malignancy was 15% (95% CI 11-19), 11% (95% CI 7.2-15), and 5.0% (95% CI 2.8-8.2), respectively. In multivariate analyses, IFN treatment was associated with a decreased risk for all cancers (Fine and Gray regression model, subdistribution Hazard Ratio (sdHR) 0.53 (95% CI 0.29-0.97); p = 0.038), a familial history of cancer was a risk factor for solid cancers (sdHR 2.12 (95% CI 1.15-3.91); p = 0.017), a personal history of cancer was a risk factor for hematological malignancies (sdHR 3.47 (95% CI 1.14-10.55); p = 0.028). Even after excluding non-melanoma skin cancers and MGUS, there was an excess of cancers (SIR = 2.22), solid cancers (SIR = 1.81) and hematological malignancies (SIR = 6.67). Conclusions: In this updated real-world retrospective cohort with a long follow-up and most pts treated with PNA, we highlighted the importance and the excess of second cancers in HCL patients, in particular hematological malignancies. Figure Disclosures Paillassa: Janssen: Other: Bibliography board with young hematologists. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Hermine:AB Science: Membership on an entity's Board of Directors or advisory committees. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support.

scholarly journals Prevalence and Risk Predictive Factors of Comorbid Malignancies in Patients with Chronic Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1900-1900
Author(s):  
Tong-Yoon Kim ◽  
Sung-Eun Lee ◽  
Soo-Hyun Kim ◽  
Soo-Young Choi ◽  
Eun-Jung Jang ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Medical Records ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Advisory Committees ◽  
History Of

Abstract Introduction: As chronic myeloid leukemia (CML) patents are generally diagnosed at old age and live longer by active use of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the occurrence of other malignancy (OM) is becoming a critical issue as a long-term comorbidity. An increased rate of OM has been reported in myeloproliferative disorders and long-term TKI treatment may induce OM in CML. To explore exact prevalence and characteristics of OM, we reviewed medical records of CML patients and compared with those of age-matched Korean population. Methods: The medical records of 1,469 CML patients who diagnosed between January 2000 and December 2014 were reviewed using Korean data-set of Asia CML Registry (ACR). With a cut-off date of July 2016, age-standardized prevalence rates (A-SPR) of OM (except benign tumors and other leukemias) were analyzed and compared with that of general population in Korea Central Cancer Registry (KCCR). In addition, we analyzed cumulative incidence rate of OM and various risk factors. Results: The median duration of follow-up was 84 (1-197) months, and 96 CML patients had at least one OM. Forty three patients had a history of OM before a median 69 (1-161) months of CML diagnosis and 53 patients developed OM after a median 53 (range; 0.2-172) months of CML diagnosis. The OM included 32 thyroid cancers, 19 colorectal cancers, 16 stomach cancers, 9 breast cancers, 4 gynecological cancers (3 cervical cancers and 1 uterine endometrial cancers), 3 lymphoma (2 non-Hodgkin's lymphoma and 1 Hodgkin's lymphoma), 3 biliary cancer, 3 skin cancers, 3 prostate cancers, 2 lung cancer, 2 tongue cancer, 2 liver cancer, 2 esophageal cancer, 1 pancreatic cancer, and 1 bladder cancer.A-SPR of OM was 1.7 times higher in CML patients. Hodgkin's lymphoma (8.7 times), thyroid cancer (2.6 times), biliary cancer (2.6 times), colorectal cancer (2 times), non-Hodgkin's lymphoma (1.8 times), cervical cancer (1.8 times), and breast cancer (1.6 times) had a higher A-SPR. On the other hands, skin cancer (3.3 times), lung cancer (2 times), and liver cancer (2 times) were lower than that of general population. With 53 patients who had OM after CML diagnosis, we analyzed the cumulative incidence. The risk of OM was increased over the follow-up period (2.7% at 7 years) Univariate analysis revealed that patients who were more than 37 years old at CML diagnosis (4.3% vs. 0.4%, p<0.001) and who had family history of cancer (8.2% vs. 2.3%, p=0.002) were associated with a higher OM. After adjusting for factors, multivariate analysis showed that older age (HR of 4.19, P<0.001) and family history (HR of 3.17, P=0.001) were independently associated with increased risk. There was no difference in 7-year overall survival (OS) between patients with OM (n=96) and without OM (n=1,373) (84.9% vs. 86.9%, p=0.573). However advanced cancer stages (stage 3 and 4) of OM significantly affected poor OS ( 88.3% vs. 65.6% P=0.0406). Conclusion: Although comorbid malignancies did not significantly affect CML survival, poor survival in advanced stages and the high risk of other cancers warn the need of systematic screening in long-term CML survivors. In addition, the specific cancer types with a significantly higher A-SPR should be considered for further studies including genetic mechanisms. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Facing Deep Venous Thrombosis (DVT) in University Tertiary Hospital: Role of Conventional Thrombophilia Testing in Idiopathic DVT Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4958-4958
Author(s):  
Milagros Suito ◽  
Maria Cerdá ◽  
Olga Benítez ◽  
Alba Cabirta ◽  
Francesc Bosch ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Board Of Directors ◽  
Research Funding ◽  
Study Group ◽  
Advisory Committees ◽  
Positive Study ◽  
Prothrombin Mutation ◽  
History Of ◽  
Thrombophilia Testing

INTRODUCTION: Deep venous thrombosis (DVT) is a frequent cause or morbidity and mortality, and multiple genetic and environmental factors are involved in its etiopathogenesis. According to it, besides investigating about personal and familiar DVT history, thrombophilia testing is often asked by physicians in order to diagnose patients, even if current validated markers can't predict the risk of recurrence of the disease. METHODS: We developed an observational and prospective study between January 2017 and December 2017, in order to register the patients with DVT that were treated in our DVT unit. As secondary objectives, we wanted to know how many had an idiopathic DVT, if we tested all of them for thrombophilia, which of them stopped treatment and the results after one year of follow up. RESULTS: We included 172 patients with DVT, 56.9% were men, and the average age was 66.4 years old with an increased incidence above the 50 years old. In our study group we found 43.6% (75) of patients without major risk factors for DVT, classified as idiopathic DVT and we will refer to them in this abstract from now on. Just 36.7% of them had a positive personal history of DVT and 36.7% had familiar history. Almost all were localized in the lower limbs (98.7%) and 17.3% presented in association with pulmonary embolism (PE) at diagnosis. All of them started treatment with LMWH, and after the first clinical visit, 26.7% continued with it, while 51.2% changed to VKA and 22.1% to DOACs. Only 45 (60%) of idiopathic DTVs were tested for thrombophilia (patients younger than 60 years old, with extensive DVT, or personal or familiar history of DVT): 31 had a negative study, 11 had a positive study for hereditary thrombophilia (4 S protein deficiency, 3 C protein deficiency, 2 V Leiden factor mutation + prothrombin mutation, 1 V Leiden factor mutation, 1 prothrombin mutation), and 3 were diagnosed of antiphospholipid syndrome. All these patients with positive study or antiphospholipid syndrome received indefinite anticoagulation. From all the patients with idiopathic DVT, 77.3% received indefinite anticoagulation, 17.3% were treated for 3-6 months, 4% for >6-12 months and 1,3% for 15 months. Only one patient who stopped treatment after 3 months had a recurrent DVT and had to restart it. CONCLUSIONS: DVT is the most frequent indication for thrombophilia testing and regarding its multifactorial etiology, it must be performed specially in incidental cases. In our incidental DVT study group (with PE associated or not), we found a 31.1% of positive studies, consistent with what is expected in general DVT population, but in contrast with it is described in the literature, we found more cases of S and C deficiency than V Leiden factor and prothrombin mutations. We also had only one patient with recurrence DVT after few months of stopping anticoagulation, no thrombophilia was found. This low rate of recurrence that differs from the latest data published, might be explained by the short time of follow up that we have, so it would be interesting to increase it, as well as the number of patients in the cohort studied. There is a need for investigating new clinical and genetic scores in order to improve the poor predictive role in recurrent disease with the current thrombophilia markers. Disclosures Bosch: F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Myelofibrosis in Real Life: Findings from the French Intergroup of Myeloproliferative Neoplasms (FIM) Registry

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3128-3128
Author(s):  
Brigitte Dupriez ◽  
Sylvie Chevret ◽  
Jean-Christophe Ianotto ◽  
Francoise Boyer ◽  
Pascale Cony-Makhoul ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Spleen Size ◽  
Biological Parameters ◽  
Advisory Committees ◽  
History Of

Abstract Background: Myelofibrosis (MF) is the less frequent Philadelphia-negative myeloproliferative neoplasms (MPN). We have included in a nationwide database primary (P), post-polycythemia (PPV) and post-essential thrombocythemia (PET) MF diagnosed in France since 2005. Methods: Inclusion criteria were: diagnostic of MF after 2005; according strictly to WHO (bone marrow biopsy mandatory); informed consent. The registry was launched in Oct. 2013, and 26 hematology centers included patients (pts). Summary statistics were reported, namely median [Interquartile range, IQR] or percentage. Baseline characteristics were compared across IPSS groups using chi-square test or Mann and Whitney test. Kaplan-Meier survival curves were plotted and compared by the log-rank test. Results: At time of analysis (June 2016) a total of 527 pts were included in the registry, complete baseline data were available in 499 (95%), and follow-up (FU) data in 433 (87%). Median [IQR] age and M/F sex ratio were 71 [63-78] years and 315/184 (1.7), respectively (resp). 301 (60%) pts had PMF, 182 (36%) had secondary MF (including 64 PPVMF and 118 PETMF) and 16 had pre-fibrotic MF. Five percent of pts had a familial history of hematologic malignancy, and 22% a history of thrombosis or hemorrhage. Splenomegaly was present in 386 (77%) with a median [IQR] spleen size of 4 cm [1-8] below costal margin, and was symptomatic in 11% of pts. Constitutional symptoms were present in 107 (21%) (weight loss in 56, night sweats in 61, fever in 14), and ECOG score was 0, 1, 2, and 3 in 53%, 36%, 11% and 0.3% of pts, resp. Median [IQR] Hemoglobin, WBC and platelet counts were 109 g/L [94-122], 9.3 G/L [5.7-16.0] and 257 G/L [138-430], resp. Circulating blast cells were present in 41%, LDH was above normal value in 95% of pts, median EPO level was 54 [11 - 57] U/L. Grade of fibrosis (WHO) was 1, 2, and 3 in 2%, 66% and 32% of pts, resp. Karyotype was done in 321 pts, normal in 173 (54%), abnormal with favorable prognostic value in 89 (30%) and unfavorable in 30 (10%) (29 failures). A total of 461 (92%) pts had molecular testing: 60% were JAK2V617F positive, 4% had MPL and 7% had CALR mutations, and 99 (28%) over the 352 pts with triple testing were triple negative. IPSS risk categories were low, int-1, int-2 and high in 68 (14%), 168 (34%), 158 (32%), and 105 (21%) pts, resp. In addition to constitutional symptoms, there was a significant increase in the prevalence of clinical signs across IPSS categories (from low to high risk): symptomatic spleen (p=0.016) -though no difference in spleen size was found (p=0.18)-, early satiety (p=0.013), ECOG score (p= 0.0001), bone pain (p=0.002). Moreover, among biological parameters, there was an increase across IPSS groups in WBC (p=0.029), LDH (p=0.0007), ferritin (p=0.003), circulating CD34+ cells (p=0.020), EPO level (p=0.035). In contrast, a decrease was seen for hemoglobin and platelets (p=0.0001 for both). Lastly, frequency of grade 3 fibrosis increased with IPSS (p=0.043), while no evidence of difference was found regarding abnormal karyotype and mutational pattern. Median FU was 33 months [9-63 months]. Among those 433 pts with FU data, median FU was 38 months [19-68], and 124 (29 %) pts had died at the time of analysis, including 13%, 17%, 31%, and 40% of pts from the Low, Int-1, Int-2, and High risk groups, resp (p= 0.0001, figure 1). In the 450 pts with treatment data, treatments received during FU included cytoreductive drug (41%), Jak-inhibitors (35%), Interferon alpha (18%), IMIDs (4%). Splenectomy was performed in only 14 (3%) pts. Forty percent of pts received packed red blood cells, and 12% platelets transfusions. 49 (11%) patients participated in a clinical trial, and 27 (6%) were allografted. Conclusion: This is the first analysis of the French MF observatory after inclusion of more than 500 pts diagnosed and treated during the past 10 years. Complete baseline data and follow-up information available for the majority of pts should allow for new studies of outcomes and influence of clinical and biological parameters, as well as reassessment of prognostic models in the era of new targeted therapies. Figure 1 Comparison of overall survival according to IPPS Figure 1. Comparison of overall survival according to IPPS Figure 2 Figure 2. Disclosures Etienne: Pfizer: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Tavitian:Novartis: Membership on an entity's Board of Directors or advisory committees. Ugo:Novartis: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Risk Factors for the Development of High-Titer Inhibitors in 260 Children with Severe Hemophilia a Born Between 1990 and 2009: The Remain Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3774-3774
Author(s):  
Maria Elisa Mancuso ◽  
Kathelijn Fischer ◽  
Elena Santagostino ◽  
Johannes Oldenburg ◽  
Helen Platokouki ◽  
...  
Keyword(s):  
Family History ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
High Dose ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
History Of

Abstract The development of anti-FVIII antibodies (i.e., inhibitors) is the major side effect of severe hemophilia A treatment. Inhibitors mainly develop in children during the first 50 exposure days and are classified in low-and high-titer (i.e., peak titer < or > 5 UB/ml). High-titer inhibitors have the major clinical impact. At diagnosis however, the real nature of the antibody is not clear in all patients, since some low-titer inhibitors may progress to high-titer. The determinants of the evolution from low- to high-titer inhibitors are still unclear and the aim of the present study was to investigate potential risk factors associated with the progression from low- to high-titer inhibitors. This study is a follow-up study of the PedNet Registry and includes 260 children with severe hemophilia A and clinically relevant inhibitors, born between 1990 and 2009 and consecutively recruited from 31 hemophilia centers in 16 countries. Clinical and laboratory data were collected from the date of first positive inhibitor test and covered a minimum of 3-years follow-up. Factors potentially associated with progression from low- to high-titer inhibitor development were analyzed using univariate and multivariate logistic regression. F8 mutation type was known in 247 patients (95%), including 202 (82%) null mutations (i.e., large deletions, nonsense mutations and inversions). Positive family history of inhibitors was present in 37 of 99 (37%) with positive family history of hemophilia. At diagnosis 49% (n=127) had low-titer inhibitors, however, upon FVIII re-exposure, 50% of low-titer inhibitors progressed to high-titer and only 25% of patients (n=69) had persistent low-titer inhibitors. Within the first 3 years of follow-up, immune tolerance induction (ITI) was equally implemented in around 80% of low-and high-titer patients but it was started later in children with high-titers (median time to ITI start 4.5 vs 0.3 months; p<0.001) in whom daily regimens and high-dose FVIII were more frequently adopted (89, 67% vs 41, 50% and 98, 74% vs 35, 43%; p=0.01 and <0.001, respectively). Overall high-titer inhibitor development was associated with null F8 mutations (OR 2.8, 95%CI 1.4-5.5) and family history of inhibitors (OR 3.9, 95%CI 1.2-12.6). The progression from low- to high-titer inhibitors during follow up, was associated with the use of high-dose ITI regimens (i.e., >100 IU/kg/day) with an OR of 3.9 (95%CI 1.5-10.0), independent from the effects of F8 mutation type (adjusted OR 3.6, 95%CI 1.4-9.8) and family history of inhibitors (adjusted OR 6.7, 95%CI 1.1-42.6). No difference was found by comparing the use of daily versus non-daily ITI. In conclusion, in a cohort of 260 children with severe hemophilia A and inhibitors, 49% presented with low-titers at diagnosis and 46% of them progressed to high-titers during follow-up. Progression to high-titer inhibitors was associated with the use of high-dose ITI. These results suggest that intensive ITI should be avoided as initial strategy in low-titer inhibitor patients. Disclosures Mancuso: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi/Biogen Idec: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Consultancy. Fischer:Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Santagostino:Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Sobi: Consultancy; Biogen Idec: Consultancy; Roche: Consultancy; Grifols: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy. Escuriola:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding. Liesner:BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Nolan:Sobi: Research Funding; Biogen: Research Funding.

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